Method for preventing nasolacrimal duct obstruction

ABSTRACT

The invention is directed to a method for preventing nasolacrimal duct obstruction (NLDO) in a patient receiving high dose radioactive iodine for treatment of cancer which comprises administering to the eyes of said patient an effective amount of perchlorate anion.

BACKGROUND OF THE INVENTION

A. Field of the Invention

The invention relates the prevention of radiation injury to tissuesexpressing the protein sodium/iodide symporter (NIS) and especially toradiation injury to the lacrimal sac and nasolacrimal duct in cancerpatients being treated with high dose radioactive iodine.

B. Description of the Related Art

The sodium-iodide symporter is an integral membrane protein that residesin the basolateral membrane of epithelial cells located in such organsas the thyroid. The sodium-iodide symporter cannot distinguish betweennormal and radioactive iodide, thus providing a useful exploit fordiagnosis and treatment of certain thyroid disease. Small amounts ofradioactive iodine (I¹²³) injected into patients are rapidlyconcentrated in the thyroid, providing a means to image the thyroid fordetection of tumors and other abnormalities. Administration ofradioiodine (I¹³¹) is widely used for treatment of hyperthyroidism andsome types of thyroid cancer; in this case the radioactivity isconcentrated rather precisely in the tissue requiring destruction.

The sodium-iodide symporter simultaneously transports both Na+ and I−ions from extracellular fluid (i.e. blood) into the thyroid epithelialcell. This process is an example of secondard active transport. Energyis provided by the electrochemical gradient of sodium across the cellmembrane; the low intracellular concentration of sodium is maintained bysodium pumps. Although, the sodium-iodide symporter is most highlyexpressed in thyroid epithelial cells, lower levels of expression can bedetected in mammary gland, salivary gland, stomach and colon tissue. SeeU.S. Pat. No. 6,803,199, Col. 1 and 2.

Ophthalmic complications following I¹³¹ radiation therapy have beenobserved in a significant percentage of patients being treated forthyroid cancer. Symptoms such as ocular dryness, epiphora (watering ofthe eyes due to obstruction of the lacrimal passages), dry mouth(xerostomia) and nasolacrimal duct obstruction (NLDO) have beenobserved. Kloos et al, J Clin Endocrinol Metab. 2002 December; 87(12):5817-20 and Burns et al, Opthal Plast Reconstr Surg. 2004 March; 20(2):126-9.

It is believed that the cases of NLDO observed in some patientsreceiving high dose radioiodine treatment is due to the concentration ofradioactivity by the sodium-iodide symporter. High levels ofradioactivity concentrated by NIS in a relatively small area in thelacrimal sac and nasolacrimal duct causes fibrosis which results inblockage in the lacrimal duct and nasolacrimal sac. It is also believedthat some cases of dry mouth observed in patients being treated withhigh does radioiodine for head and neck cancers is due to accumulationof radioactivity in the salivary glands leading to fibrosis which blocksrelease of the salivary fluids.

The incidence of newly diagnosed head and neck cancers (excluding skincancers) in the US is estimated at more than 50,000 cases annually. Themost common type of cancer in the head and neck is squamous cellcarcinoma, which arises in the cells that line the inside of the nose,mouth, and throat. Other less common types of head and neck cancersinclude salivary gland tumors, lymphomas and sarcomas. In addition tohead and neck cancers, there are over 15,000 new cases of thyroid cancereach year in the United States.

Thyroid cancer is typically treated with surgery followed by radiationtherapy. The three main types of treatment for managing head and neckcancer are radiation therapy, surgery and chemotherapy with the primarytreatment being radiation therapy or surgery, or both combined.

In addition to being used in the treatment of head and neck and thyroidcancers, radioactive iodine (I¹³¹) is widely used to treathyperthyroidism. Hyperthyroidism results from excess quantities ofthyroid hormone within the body. Rather than being classified as aspecific disease, it is classified as a syndrome that describes thecharacteristics resulting from this condition. The causes ofhyperthyroidism include Graves' disease; tumors of the thyroid gland,pituitary gland, testes or ovaries; inflammation of the thyroid from aviral infection or other inflammation; ingestion of excessive amounts ofthyroid hormone; and ingestion of excessive iodine. Graves' diseaseaccounts for 85% of all cases of hyperthyroidism. The incidence is 1 outof 1,000 people.

Finally, doctors are increasingly using radioiodine to treat breastcancer. Radioactive I¹³¹ is given either orally or by injection. UsingI¹³¹, the clinician is able to selectively target the cancerous breasttissue as opposed to normal breast tissue. The reason for this is thatalthough normal breast tissue has some expression of NIS, cancerousbreast tissue expresses the protein at higher amounts. The result is bytreating patients with I¹³¹ the cancerous breast tissue will receivemore amounts of the radioactivity then the surrounding normal tissue. Bycontrolling the amount of I¹³¹ given to the patient, it may be possibleto keep the level of toxicity to the normal tissue low while reachinghigh enough levels in the cancerous tissue to destroy the canceroustissue.

In the United States each year, as many as 100,000 people may be treatedwith high dose I¹³¹. This number is expected to increase as the use ofI¹³¹ to treat breast cancer because more common. With the increased useof high dose radioiodine, it is expected that the incidence of NLDO willincrease as well.

The traditional procedure most often relied on for relief of NLDO isincisional dacryocystorhinostomy (DCR). This procedure has a number ofdrawbacks: recovery time is significant, an incisional scar may developdue to invasive procedures, there is potential for excess bleeding, theprocedure must be done under anesthesia usually general anesthesia, andthe costs associated with the surgical procedure are not trivial. TheDCR procedure has a high success rate in patients suffering from NLDOcaused by other than high dose radioiodine; however, in patients wherethe nasolacrimal duct is obstructed as a result of receiving high doseradioiodine, the DCR procedure does not work very well.

Currently, there is not available a safe and effective method forpreventing the fibrosis that can occur in the nasolacrimal duct area dueto the administration of high dose radioiodine. A method that preventsor reduces the formation of fibrosis in the nasolacrimal duct ratherthan treats fibrosis after it forms, is highly desirable. The method ofthe invention described herein avoids all of the drawbacks associatedwith DCR. It is a cost effective, safe, non-invasive method thatutilizes topical application of perchlorate anion in ophthalmicsolutions, ophthalmic creams or gels to block the ability of thesodium-iodide symporter to concentrate radioactivity. The method of theinvention is so safe and effective and cost effective that it should bethe standard of care for every patient receiving high does I¹³¹ therapyfor treatment of cancer and especially for treatment of head and neck,thyroid and breast cancers.

SUMMARY OF THE INVENTION

The invention is directed to a method for preventing nasolacrimal ductobstruction (NLDO) in a patient receiving high dose radioactive iodinefor treatment of cancer, especially for treatment of thyroid, head andneck and breast cancers which comprises administering to the eyes ofsaid patient an effective amount of perchlorate anion.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a simplified representation of the nasolacrimal systemanatomy. Tears are produced in the lacrimal gland 1, flow through ducts2 leading to the surface of the eyeball 3 and spread over the surface ofthe eyeball 3. When one blinks the upper and lower eyelids 4 and 5 pushthe tears which also contain proteins and sugars to the inside corner ofthe eye. There are two openings at the inside corner of each eye nearthe nose, the superior puncta 6 and inferior puncta 7 which open intothe vertical caniculi 8. The vertical caniculi 8 bend at right angles atthe superior ampulla 9 and inferior ampulla 10 and form the horizontalcaniculi 11. The horizontal caniculi 11 drain tears and other fluidsinto the lacrimal sac 11 which is connected with the nasolacrimal duct12 and which opens into the nose 13.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to a method for preventing nasolacrimal ductobstruction (NLDO) in a patient receiving radioactive iodine andespecially high dose radioactive iodine for treatment of cancer whichcomprises administering to each eye of said patient an effective amountof perchlorate anion.

A further embodiment of the invention is directed to a method forpreventing nasolacrimal duct obstruction (NLDO) in a patient receivinghigh dose radioactive iodine (I¹³¹) treatment for thyroid, head and neckand breast cancer which comprises administering to each eye of saidpatient an effective amount of perchlorate anion, wherein the patient ispre-treated with perchlorate anion for a period of from about 3 to about5 days prior to initiation of high dose I¹³¹ therapy, wherein treatmentwith perchlorate anion continues for as long as the patient receiveshigh dose radiation therapy, and wherein treatment with perchlorateanion is continued for from about 3 to about 5 days after cessation ofradiation therapy.

The term “nasolacrimal duct obstruction” (NLDO) as used herein to refersto a blockage in the distal horizontal caniculi 10, lacrimal sac 11and/or the nasolacrimal duct 12 which prevents liquid from draining intothe nose. As a result of the blockage there is a buildup of tears,containing mucin, sugars and other components such as bacteria in theareas just described leading to irritation and infection.

Symptoms of NLDO are epiphora (excessive tearing) due to a decrease intear draining, inflammation and infection (dacryocystitis) of thelacrimal sac. The area beneath the eyes next to the nose can become red,inflamed, and sensitive to the touch. The area usually is swollen, andthere may be a mucous discharge from the opening of the nasal corner ofthe eye. Common complaints include itching, irritation, burning,redness, conjunctivitis and pain.

As used herein the term “high dose” radioactive iodine (RAI) refers tocumulative doses of radioactive iodine (I¹³¹) of about 150 mCi orgreater. Although, iodine can be made into two radioactive isotopes formedical uses: I¹²³ and I¹³¹, the radiation that 1123 gives off isgenerally used in scanning or imaging rather than for treatment. The RAIthat is most often used in chemotherapy is I¹³¹. It is usuallyadministered to the patient by mouth either as a capsule or a liquid orintravenously (IV). RAI that is not concentrated in tissue is eliminatedfrom the body through sweat and urine.

The term “perchlorate anion (ClO4−)” as used herein refers to the anionthat is produced when solid salts of ammonium, potassium, and sodiumperchlorate, and perchloric acid are dissolved in an aqueous liquid.

The term “effective amount” is used herein to mean an amount ofperchlorate anion sufficient to reduce or inhibit fibrosis in the distalcaniculi, lacrimal sac and/or nasolacrimal duct caused by theconcentration of radioactivity by the NIS protein in a patient receivingradioiodine therapy. Any source of perchlorate ion may be used in themethod of the invention. However, potassium perchlorate and sodiumperchlorate are preferred for use in the methods of the inventionbecause they are in use in other approved pharmaceutical applicationsand pharmaceutical grade (USP) compound is readily available.Administration of perchlorate anion to the patient should be startedfrom about 3 to 5 days prior to the initiation of I¹³¹ chemotherapy andshould continue during the course of chemotherapy and for 3 to 5 daysafter cessation of I¹³¹ therapy.

Preferred for use in the method of the invention are ophthalmicmedicaments containing from about 10 mg/ml to about 500 mg/ml ofpotassium perchlorate (KClO₄) or sodium perchlorate (NaClO₄) andpreferably from about 40 mg/ml to about 400 mg/ml and more preferablyfrom about 50 mg/ml to from about 100 mg/ml.

The ophthalmic medicament containing the perchlorate anion is topicallyadministered in the corner of the eye near the superior and inferiorpuncta 6 and 7. The perchlorate anion may be administered topically tothe eye as for example a sterile liquid e.g., an eye wash or eye drops,an aqueous gel, or ophthalmic ointment or cream. As would be recognizedby one skilled in this art, any ophthalmic formulation that is sterileand that is pharmaceutically acceptable, i.e., is safe and effective forits intended purpose may be used to deliver perchlorate anion to thelacrimal sac and nasolacrimal duct.

The maximum volume of the lacrimal sac is about 30 μl. The averagevolume of a human tear is 7 μl. Most commercially eye drops have a perdrop volume in the range of from 50-75 μl. If the droplet volume is muchexcess of 75 μl it probably will not get into the lacrimal sac and thus,the nasolacrimal duct, and the excess solution will be wasted as itdrips out of the eye and down the face. Ideally, an eye drop solutionwill have a high concentration of drug in a minimum drop volume.Multiple drops administered at intervals, produces higher drugconcentrations in the lacrimal sac and nasolacrimal duct.

An alternative to a solution of perchlorate anion for use in the methodsof the invention is an ophthalmic ointment containing the perchlorateanion. An advantage of an ointment is that it has a longer contact timewith the eye and potentially greater total drug bioavailability. Sincean ointment can interfere with vision it is best used at bedtime. Theperchlorate is added to the ointment base as a solution or a micronizedpowder. Most ophthalmic ointments are prepared with a base of whitepetrolatum and mineral oil, often with anhydrous lanolin. Some contain apolyethylene-mineral oil gel. Whatever base is used, it must benonirritating to the eye, permit diffusion of the drug throughout theeye and retain activity of the perchlorate for a reasonable period oftime upon storage.

The ophthalmic medicament containing perchlorate anion may be selfadministered or it may be administered by the clinician, in which caseit may be instilled directly into the lacrimal sac and nasolacrimalduct.

As would be recognized by one skilled in this art, it is within theskill of the art to prepare sterile, shelf-stable ophthalmic solutions,gels and ointments. See for example, Remington's Pharmaceutical Sciences18^(th) Ed., Alfonso Gennaro Editor, 1990, Mack Publishing C., Easton,Pa. 18042, pp. 1581-1595 (now known as Remington: The Science andPractice of Pharmacy, 20th Edition, Alfonso Gennaro Editor, LippincottWilliams & Wilkins, Baltimore, Md.) for information regarding theproperties of, and the preparation of, ophthalmic solutions andointments.

Both potassium perchlorate and sodium perchlorate are in use to minimizeor reduce accumulation of technetium or I¹²³ in certain tissues inpatients undergoing imaging studies. Potassium perchlorate is availablefrom Mallinckrodt Inc. St. Louis, Mo. 63134 under the trade namePerchloracap®. Perchloracap is supplied for use during diagnosticstudies as an opaque gray gelatin capsule for oral administration. Eachcapsule contains 200 milligrams of potassium perchlorate (KClO₄) mixedwith an inert filler. Perchloracap is administered to minimize theaccumulation of pertechnetate Tc 99m in the choroid plexus and in thesalivary and thyroid glands in patients receiving sodium pertechnetateTc 99m injection for brain and blood pool imaging and placentalocalization.

Sodium perchlorate is manufactured in the United Kingdom by Torbay PMU,a division of the South Devon Healthcare Trust and is available in theUK as a 20 mg/ml solution for injection. Sodium Perchlorate Injection isused as a thyroid blocking agent for patients unable to toleratealternative oral thyroid blocking agents when undergoing studies withradioiodinated radiopharmaceuticals known to de-iodinate in vivo.

Although potassium and sodium perchlorate have been used to blockaccumulation of technetium 99m and I¹²³ in the thyroid gland, choroidplexus, and salivary glands there is no recognition in the art thatperchlorate may reduce or eliminate fibrosis that can occur in thenasolacrimal area in patients receiving high dose radioiodine fortreatment of various cancers.

The invention and the manner and process of making and using it are nowdescribed in such full, clear, and concise terms as to enable any personskilled in the art to which it pertains to make and use same. It is tobe understood that the forgoing describes preferred embodiments of thepresent invention and that modifications may be made therein withoutdeparting from the spirit or scope of the present invention as set forthin the claims. To particularly point out and distinctly claim thesubject matter regarded as the invention, the following claims concludethis specification.

1. A method for preventing nasolacrimal duct obstruction in a patientreceiving high dose radioactive iodine for treatment of cancer whichcomprises topically administering to the eyes of said patient atherapeutically effective amount of perchlorate anion; wherein saidPerchlorate anion is administered at a dosage of from about 10 mg/ml toabout 400 mg/ml and wherein said patient does not have congenitalnasolacrimal duct obstruction.
 2. The method according to claim 1wherein said radioactive iodine is I¹³¹.
 3. The method according toclaim 2 wherein the cumulative dose of I¹³¹ given to the patient isgreater than 150 mCi.
 4. The method according to claim 2 wherein thesource of said perchlorate anion is a compound selected from the groupcomprising potassium perchlorate, sodium perchlorate, ammoniumperchlorate and perchloric acid.
 5. (canceled)
 6. The method accordingto claim 4 wherein said perchlorate compound is administered at a dosageof from about 40 mg/ml to about 400 mg/ml.
 7. The method according toclaim 6 wherein said perchlorate compound is administered at a dosage offrom about 50 mg/ml to about 100 mg/ml.
 8. The method according to claim2 wherein said perchlorate anion is administered to the eyes of saidpatient for from about 3 days to about 5 days prior to initiation oftreatment with high dose radioactive iodine and wherein said perchlorateanion treatment is continued for as long as said patient receives highdose radioactive iodine and wherein said perchlorate anion isadministered to the eyes of said patient for from about 3 days to fromabout 5 days after high dose radioactive iodine treatment isdiscontinued.
 9. The method according to claim 1 wherein saidperchlorate anion is administered to the eyes of said patient as atopical liquid, gel, cream or ointment.
 10. The method according toclaim 3 wherein said cancer is selected from the group consisting ofhead and neck cancer, thyroid cancer and breast cancer.
 11. A method forpreventing nasolacrimal duct obstruction in a patient receiving highdose I¹³¹ for treatment of cancer which comprises topicallyadministering to the eyes of said patient an effective amount ofperchlorate anion, wherein the patient is pre-treated with perchlorateanion for a period of from about 3 to about 5 days prior to initiationof high dose I¹³¹ radiation therapy, wherein treatment with perchlorateanion continues for as long as the patient receives high dose radiationtherapy, and wherein treatment with perchlorate anion is continued forfrom about 3 to about 5 days after discontinuing radiation therapy. 12.(canceled)
 13. The method according to claim 11 wherein the source ofsaid perchlorate anion is a compound selected from the group comprisingpotassium perchlorate, sodium perchlorate, ammonium perchlorate andperchloric acid.
 14. The method according to claim 13 wherein saidperchlorate compound is administered at a dosage of from about 10 mg/mlto about 500 mg/ml.
 15. The method according to claim 14 wherein saiddosage is from about 40 mg/ml to about 400 mg/day.
 16. The methodaccording to claim 15 wherein said dosage is from about 50 mg/ml toabout 100 mg/ml.
 17. The method according to claim 11 wherein saidcancer is selected from the group comprising thyroid cancer, head andneck cancer and breast cancer.
 18. The method according to claim 11wherein said perchlorate anion is administered to the eyes as a topicalliquid, gel, cream or ointment.
 19. The method according to claim 9wherein said topical liquid or gel is administered to the eyes as anaqueous liquid or aqueous gel.
 20. The method according to claim 11wherein said radioactive iodine is I¹³¹ is administered at a cumulativedosage of 150 mCi or greater.
 21. The method according to claim 18wherein said topical liquid or gel is administered to the eyes as anaqueous liquid or aqueous gel.
 22. A method for preventing nasolacrimalduct obstruction in a patient receiving high dose I¹³¹ for treatment ofthyroid cancer, head and neck cancer or breast cancer which comprisestopically administering to the eyes of said patient a therapeuticallyeffective amount of perchlorate anion, wherein the patient ispre-treated with perchlorate anion for a period of from about 3 to about5 days prior to initiation of high dose I¹³¹ radiation therapy, whereintreatment with perchlorate anion continues for as long as the patientreceives high dose radiation therapy, and wherein treatment withperchlorate anion is continued for from about 3 to about 5 days afterdiscontinuing radiation therapy; wherein the source of said perchlorateanion is a compound selected from the group comprising potassiumperchlorate, sodium perchlorate, ammonium perchlorate and perchloricacid and wherein said perchlorate compound is administered at a dosageof from about 10 mg/ml to about 500 mg/ml; provided that said patientdoes not have congenital nasolacrimal duct obstruction.